REQUEST FOR THE EXTENSION OF MERIT AWARD R37 DA005147 TWIN FAMILY STUDY OF VULNERABILITY TO SUBSTANCE ABUSE Research Proposal Abstract During the past three years of R37 award funding, we have been completing the age-29 assessment of a population-based male twin sample followed prospectively since the twins were 11 years old. This has allowed us to examine how gene-environment interplay over the course of adolescent and young adult development affect the initiation, escalation, persistence, and desistence of nicotine, alcohol, and illicit drug misuse and abuse. In a separately funded study, we are in the process of completing a parallel assessment of female twins who have been prospectively studied over the same age range and using the same longitudinal design. When these projects are completed, we will have detailed outcome information on the mental health and psychological adjustment of our participants, and we will be able to relate these findings to their developmental history of substance use. Little is known about how this history affects brain development, and we are uniquely positioned to address this question. For this extension period, we propose undertaking a neurocognitive assessment of 360 twin pairs from both the male and female 11-year-old cohorts at a developmental time point (age 34) where they have likely established stable patterns of substance use behavior and enduring adult roles. This half-day assessment will build on the brain electrophysiological endophenotype and cognitive assessments we have been conducting in this prospective research. We will update their substance use and mental health status and document significant life changes, measure neuropsychological functioning in multiple domains, and carry out structural (anatomical and DTI), functional, and resting state magnetic resonance imaging of their brains when the twins are approximately age 34. We will examine the association between observed neurocognitive outcomes and individual differences in developmental patterns of drinking and drug use that characterized our participants during adolescence and young adulthood. From this work, we can examine adult brain outcomes associated with heavy substance use in adolescence, determine if these outcomes are different from those associated with heavy use that continues into adulthood or from heavy use that onsets after adolescence, examine outcomes associated with desistance from heavy use, and evaluate gender effects. Our twin design will allow us to model the heritability of brain-based outcomes, and importantly, understand how heritability is moderated by exposure to illicit substances and alcohol; i.e., whether exposure is associated with a gene x environment interaction such that genetic effects are attenuated or augmented by exposure to substance misuse. In addition, we will make use of a cotwin differences design which will allow us to model how within-pair differences in substance use are associated with within-pair differences in brain outcomes. Although we will be examining both monozygotic (MZ) and dizygotic (DZ) twins using this design, its value can be readily appreciated when considering results for MZ twins whose brains will differ due to nonshared environmental effects. such as those resulting from substance misuse neurotoxicity. In effect, the lesser-using twin provides an indication of what the heavier-using twin's brain would be like had the greater degree of substance exposure not occurred in the heavier using twin. The combination of prospective longitudinal and twin difference designs provides one ofthe most powerful research strategies available, allowing us to make stronger inferences about the possible neurotoxic consequences of substance misuse on brain development than are possible through traditional longitudinal designs alone. Progress Report Progress Report Overview Behavioral Disinhibition Developmental Model: This landmark project, which has produced over 150 publications, is motivated by a model that posits that an inherited liability for the development of substance use disorders (SUDs) reflects underlying disinhibitory processes that account forthe development of SUDs and related phenotypes composing an externalizing psychopathology spectrum (lacono et al., 2008). This spectrum includes personality traits associated with low constraint, risky behaviors (e.g., early sexual intercourse), antisociality, childhood disruptive disorders (e.g., ADHD, conduct disorder), and substance misuse. Those with the liability show reduced amplitude of the brain P300 response, a developmental endophenotype that is associated with all of these spectrum characteristics. This genetic liability, which accounts forthe covariance among these externalizing characteristics, is potentiated or diminished by environmental risk and protective factors. Specific genetic and environmental effects lead to the differentiation of externalizing characteristics over the course of adolescence and emerging adulthood that account for why individuals develop one SUD and not another. These developmental processes continue with adult maturation, affecting the likelihood of persisting problem substance use. R37 Aims: Our current Specific Aims call for 1) completing an assessment on our twin sample as the male twins that we have been studying since age 11 now reach age 29, 2) examining trajectories that define the course and outcomes associated with substance use disorders (SUDs) from age 11 to 29, and 3) collecting DNA for the NIDA Genetics Consortium (NGC) Repository. Aim 3 is complete, and we now have DNA on over 91% of our participants, with DNA for 85% deposited at the NGC repository. Because we are in the midst of grant Year 4, Aim 1 data collection is still ongoing, and Aim 2 analyses have begun but are not completed. However, since funding for this grant began in January 2009, we have been remarkably productive, publishing 64 papers (about 20 per year) widely distributed among premier journals in psychiatry, psychology, addiction, psychophysiology, and genetics. Most ofthese reports address themes related to gene-environment interplay affecting the development of SUDs and related phenotypes through adolescence and into young adulthood. For the proposed extension of this R37 award, we will conduct an outcome assessment targeting neurocognitive function, enabling an evaluation of how substance use in adolescence and young adulthood affects brain and cognitive outcome in adulthood. Status of Participant Recruitment and Assessment in Year 4 of this R37 Our age-29 male twin testing protocol represents the sixth in-person assessment of these participants. Beginning with intake at age 11, these longitudinal data have yielded a rich developmental data set that documents the status of our participants prior to their initiation of substance use and traces their outcomes through early adulthood. The ongoing assessment, which is nearing completion this year, consists of a 2-hour clinical interview (with self-report measures brought in at the visit) and a 2-hour lab component focused on putative endophenotypes for addiction. We expect the final participation rate to be between 87-90%. Our corresponding assessment of female twins is presently 43% complete, and is on pace to have over a 90% participation rate. The female twin assessment will be completed in 2013, before the extension ofthe R37 begins. Importantly, non-participation at one follow-up does not preclude participation in a later follow-up; only approximately 2% of twins failed to participate in at least one follow-up. Participation rates for follow-ups 1-4 have averaged over 90%, leading us to expect no more than a 10% non-participation rate for the proposed age-34 assessment.